For 20 years, systematic studies in rodents have identified specific neural substrates regulating pre-pulse inhibition (PPI) of startle, including parts of the prefrontal cortex, hippocampus, amygdala, ventral striatum and pallidum, and pontine tegmentum. These limbic cortico- striato-pallido-pontine (CSPP) substrates regulating PPI are relevant to several neuropsychiatric disorders, and are implicated in the reinforcing properties of drugs of abuse. Now that the neural substrates of PPI have been delineated in rats, the next major challenge is to develop the capacity to probe and understand this PPI-regulatory circuitry in humans. If neural circuit information, derived from animal studies, could be translated across species, PPI could become an important, new tool for understanding this circuitry in normal and neuropsychiatric disordered populations. Specific drug effects on PPI in rats are highly predictable, and are understood at the level of neural circuitry. The present proposal will initiate a translocational approach to understanding limbic CSPP circuitry, by assessing the homology of pharmacologic manipulations of PPI across species. In tests of PPI, startle habituation, latent inhibition and measures of sensory gating, we will carefully assess the time course and dose response effects of the direct dopamine (DA) agonists bromocriptine, per-golide and ropinirole, the indirect DA agonists amphetamine and amantadine, and an active comparison drug (caffeine) in normal humans. Contemporaneous measurement of physiological and psychological variables will facilitate interpretation of changes in the critical dependent measures. Based on initial results, we will assess DA agonist effects on the dependent measures after pretreatment with typical and atypical anti-psychotics. Future studies will assess the serotonergic, glutamatergic and nicotinic regulation of PPI and related measures, and sex differences and menstrual cyclicity of drug effects on these measures, in normal humans. Data from the proposed studies will provide new information for interpreting the neurochemical basis of PPI deficits in schizophrenic patients, as well as the sensitivity of these deficits to antipsychotics. By developing an important new strategy for under- standing limbic CSPP circuitry in humans, the proposed studies will have direct relevance to a broad range of issues in neuropsychiatry, including the neurobiology of drug abuse. More generally, these studies will begin the important process of examining the neuro-chemistry of sensorimotor gating processes that fundamentally shape behavior and cognition in humans.